Nrf2-regulated L-2-hydroxyglutarate sensitizes erythroid cells to ferroptosis in sickle cell disease

SCD had hemolysis with elevated levels of heme and iron, which induced ferroptosis. Here, we found Nrf2 knockout in SCD mice accumulated the levels of the metabolite L-2-hydroxyglutarate (L2HG), which impaired ferroptosis stress response to exacerbate SCD symptom. Mechanistically, L2HG was found to regulate the expression of genes involved in the iron and heme metabolism via histone epigenetic hypermethylation. Our findings indicate an important role of Nrf2/L2HG in SCD for ferroptosis response. Comparison of spleen erythroid cells transcriptome in sickle cell disease Nrf2 WT (3 samples) and Nrf2 KO mice (3 samples) at 2-3 month of age.镰状细胞病（Sickle Cell Disease, SCD）会发生溶血，伴随血红素与铁水平升高，进而诱导铁死亡（ferroptosis）。本研究发现，SCD小鼠体内的核因子E2相关因子2（Nuclear factor erythroid 2-related factor 2, Nrf2）敲除后，代谢物L-2-羟基戊二酸（L-2-hydroxyglutarate，L2HG）的水平出现蓄积，该代谢物会削弱铁死亡应激应答能力，进而加重SCD的临床症状。机制层面分析显示，L2HG可通过组蛋白表观遗传超甲基化，调控铁与血红素代谢相关基因的表达。本研究结果表明，Nrf2/L2HG通路在SCD的铁死亡应答中发挥重要作用。本数据集针对2-3月龄的镰状细胞病模型小鼠，对其脾脏红细胞转录组（transcriptome）进行了比较分析，包含Nrf2野生型小鼠3份样本与Nrf2敲除型小鼠3份样本。